Tarec K. Elajami

Targeting inflammation in metabolic syndrome

The metabolic syndrome (MetS) is comprised of a cluster of closely related risk factors, including visceral adiposity, insulin resistance, hypertension, high triglyceride, and low high-density lipoprotein cholesterol; all of which increase the risk for the development of type 2 diabetes and cardiovascular disease. A chronic state of inflammation appears to be a central mechanism underlying the pathophysiology of insulin resistance and MetS. In this review, we summarize recent research which has provided insight into the mechanisms by which inflammation underlies the pathophysiology of the individual components of MetS including visceral adiposity, hyperglycemia and insulin resistance, dyslipidemia, and hypertension. On the basis of these mechanisms, we summarize therapeutic modalities to target inflammation in the MetS and its individual components. Current therapeutic modalities can modulate the individual components of MetS and have a direct anti-inflammatory effect. Lifestyle modifications including exercise, weight loss, and diets high in fruits, vegetables, fiber, whole grains, and low-fat dairy and low in saturated fat and glucose are recommended as a first line therapy. The Mediterranean and dietary approaches to stop hypertension diets are especially beneficial and have been shown to prevent development of MetS. Moreover, the Mediterranean diet has been associated with reductions in total and cardiovascular mortality. Omega-3 fatty acids and peroxisome proliferator-activated receptor α agonists lower high levels of triglyceride; their role in targeting inflammation is reviewed. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockers comprise pharmacologic therapies for hypertension but also target other aspects of MetS including inflammation. Statin drugs target many of the underlying inflammatory pathways involved in MetS.

Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status

OBJECTIVE Soy has been associated with lower risk of cardiovascular disease in Asian countries which consume daily soy. Our study examined whether production of equol, an estrogen metabolite, affected the ability of soy nuts to improve cardiovascular risk factors. MATERIALS/METHODS Sixty postmenopausal women participated in a randomized, controlled, crossover trial of a Therapeutic Lifestyle Changes (TLC) diet alone and a TLC diet in which 0.5 cup of soy nuts (25 g of soy protein and 101 mg of aglycone isoflavones) replaced 25 g of nonsoy protein daily. Each diet was followed for 8 weeks at the end of which blood pressure (BP), lipid levels, adhesion molecules and inflammatory markers were measured. RESULTS Women with MetS had significantly higher baseline body mass index (BMI), BP, triglycerides (TG), and soluble intercellular adhesion molecule (sICAM) than women without MetS. In women with MetS on the soy diet, significant reductions in diastolic BP (7.7%; P=0.02), TG (22.9%; P=0.02), C-reactive protein (CRP) (21.4%; P=0.01) and sICAM (7.3%; P=0.03) were noted among equol producers compared to levels on the TLC diet. No significant changes were noted in equol nonproducers. Similarly, in women without MetS, only equol producers had significant reductions in diastolic BP (3.3%, P=0.02) and CRP (30%, P=0.04). In contrast to women with MetS, TG and sICAM levels were not affected in women without MetS, a finding possibly related to lower baseline levels. CONCLUSIONS Cardiovascular risk reduction with soy nuts is not uniform and may be greater among producers of equol.

Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling

Inflammation in arterial walls leads to coronary artery disease (CAD). Because specialized proresolving lipid mediators (SPMs; lipoxins, resolvins, and protectins) stimulate resolution of inflammation in animal models, we tested whether n‐3 fatty acids impact SPM profiles in patients with CAD and promote clot remodeling. Six patients with stable CAD were randomly assigned to either treatment with daily 3.36 g Lovaza for 1 yr or without. Targeted lipid mediator‐metabololipidomics showed that both groups had absence of resolvin D1 (RvD1), RvD2, RvD3, RvD5 and resolvin E1—all of which are present in healthy patients. Those not taking Lovaza had an absence of aspirin‐triggered resolvin D3 (AT‐RvD3) and aspirin‐triggered lipoxin B4 (AT‐LXB4). Lovaza treatment restored AT‐RvD3 and AT‐LXB4 and gave levels of RvD6 and aspirin‐triggered protectin D1 (AT‐PD1) twice as high (resolvin E2 ~5 fold) as well as lower prostaglandins. Principal component analysis indicated positive relationships for patients with CAD who were receiving Lovaza with increased AT‐RvD3, RvD6, AT‐PD1, and AT‐LXB4.SPMs identified in Lovaza‐treated patients with CAD enhanced ~50% at 1 nM macrophage uptake of blood clots. These results indicate that patients with CAD have lower levels and/or absence of specific SPMs that were restored with Lovaza; these SPMs promote macrophage phagocytosis of blood clots. Together, they suggest that low vascular SPMs may enable progression of chronic vascular inflammation predisposing to coronary atherosclerosis and to thrombosis.—Elajami, T. K., Colas, R. A., Dalli, J., Chiang, N., Serhan, C. N., Welty, F. K. Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. FASEB J. 30, 2792‐2801 (2016). www.fasebj.org

Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial

Background Although statins reduce cardiovascular events, residual risk remains. Therefore, additional modalities are needed to reduce risk. We evaluated the effect of eicosapentaenoic acid and docosahexaenoic acid in pharmacologic doses added to statin treatment on coronary artery plaque volume. Methods and Results A total of 285 subjects with stable coronary artery disease on statins were randomized to omega‐3 ethyl‐ester (1.86 g of eicosapentaenoic acid and 1.5 g of docosahexaenoic acid daily) or no omega‐3 (control) for 30 months. Coronary plaque volume was assessed by coronary computed tomographic angiography. Mean (SD) age was 63.0 (7.7) years; mean low‐density lipoprotein cholesterol ≤80 mg/dL. In the intention‐to‐treat analysis, our primary endpoint, noncalcified plaque volume, was not different between groups (P=0.14) but approached significance in the per protocol analysis (P=0.07). When stratified by age in the intention‐to‐treat analysis, younger omega‐3 subjects had significantly less progression of the primary endpoint, noncalcified plaque (P=0.013), and fibrous, calcified and total plaque. In plaque subtype analysis, controls had significant progression of fibrous plaque compared to no change in the omega‐3 ethyl‐ester group (median % change [interquartile range], 5.0% [−5.7, 20.0] versus −0.1% [−12.3, 14.5], respectively; P=0.018). Among those on low‐intensity statins, omega‐3 ethyl‐ester subjects had attenuation of fibrous plaque progression compared to controls (median % change [interquartile range], 0.3% [−12.8, 9.0] versus 4.8% [−5.1, 19.0], respectively; P=0.032). In contrast, those on high‐intensity statins had no difference in plaque change in either treatment arm. Conclusions High‐dose eicosapentaenoic acid and docosahexaenoic acid provided additional benefit to statins in preventing progression of fibrous coronary plaque in subjects adherent to therapy with well‐controlled low‐density lipoprotein cholesterol levels. The benefit on low‐intensity statin, but not high‐intensity statin, suggests that statin intensity affects plaque volume. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01624727.

Eicosapentaenoic and Docosahexaenoic Acids Attenuate Progression of Albuminuria in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Background Albuminuria is a marker of inflammation and an independent predictor of cardiovascular morbidity and mortality. The current study evaluated whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation attenuates progression of albuminuria in subjects with coronary artery disease. Methods and Results Two‐hundred sixty‐two subjects with stable coronary artery disease were randomized to either Lovaza (1.86 g of EPA and 1.5 g of DHA daily) or no Lovaza (control) for 1 year. Percent change in urine albumin‐to‐creatinine ratio (ACR) was compared. Mean (SD) age was 63.3 (7.6) years; 17% were women and 30% had type 2 diabetes mellitus. In nondiabetic subjects, no change in urine ACR occurred in either the Lovaza or control groups. In contrast, ACR increased 72.3% (P<0.001) in diabetic subjects not receiving Lovaza, whereas those receiving Lovaza had no change. In diabetic subjects on an angiotensin‐converting enzyme‐inhibitor or angiotensin‐receptor blocker, those receiving Lovaza had no change in urine ACR, whereas those not receiving Lovaza had a 64.2% increase (P<0.001). Change in ACR was directly correlated with change in systolic blood pressure (r=0.394, P=0.01). Conclusions EPA and DHA supplementation attenuated progression of albuminuria in subjects with type 2 diabetes mellitus and coronary artery disease, most of whom were on an angiotensin‐converting enzyme‐inhibitor or angiotensin‐receptor blocker. Thus, EPA and DHA supplementation should be considered as additional therapy to an angiotensin‐converting enzyme‐inhibitor or angiotensin‐receptor blocker in subjects with type 2 diabetes mellitus and coronary artery disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01624727.

Ischemic stroke in a young adult with extremely elevated lipoprotein(a): A case report and review of literature

Lipoprotein(a) [Lp(a)] is an apolipoprotein(a) molecule bound to 1 apolipoprotein B-100. Elevated levels of Lp(a) are thought to be an independent risk factor for atherosclerosis and to promote thrombosis through incompletely understood mechanisms. We report a 34-year-old man with an ischemic stroke in the setting of an extremely high Lp(a) level-212 mg/dL. He developed severe carotid artery stenosis over a 6-year period and had thrombus formation post-carotid endarterectomy. To our knowledge, this case is unique because the Lp(a) is the highest reported level in a patient without renal disease. Moreover, this is the first reported case of the youngest individual with a stroke presumably related to development of carotid plaque over a 6-year period. The thrombotic complication after endarterectomy may have been related to the prothrombotic properties of Lp(a). Of note, the Lp(a) level did not respond to atorvastatin but did decrease 15% after aspirin 325 mg was added although his Lp(a) levels were variable, and it is not clear that this was cause and effect. This case highlights the need to better understand the relation between Lp(a) and vascular disease and the need to screen family members for elevated Lp(a). We also review treatment options to lower Lp(a) and ongoing clinical trials of newer lipid-lowering drugs that can also lower Lp(a).

Diastolic blood pressure predicts coronary plaque volume in patients with coronary artery disease

BACKGROUND AND AIMS Hypertension is associated with increased clinical and subclinical coronary artery disease (CAD); however, the relationship between blood pressure and coronary plaque volume is unclear. We examined the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on coronary artery plaque volume. METHODS 285 subjects with stable CAD on statin therapy underwent coronary computed tomographic angiography to measure volume of fatty, fibrous, noncalcified, calcified and total coronary plaque. RESULTS Mean (SD) age was 63.1 (7.7); mean (SD) LDL-C, 78.7 mg/dL (28.5). Compared to the highest DBP tertile (>76 mmHg), those in the lowest DBP tertile (≤68 mmHg) had lower volumes of fatty: 10.0 vs. 7.7 mm3/mm, (p trend = 0.042), fibrous: 19.6 vs. 13.8 mm3/mm (p trend = 0.011), non-calcified: 29.7 vs. 22.5 mm3/mm (p trend = 0.017) and total plaque: 37.8 vs. 25.1 mm3/mm (p trend = 0.010) whereas there was no relationship with SBP tertiles. Similarly, when examined as a continuous variable, higher DBP was a significant independent predictor of higher plaque volume after multivariate adjustment: for every 1 mmHg increase in DBP, fibrous plaque increased 0.128 mm3/mm (p = 0.022), noncalcified plaque increased 0.176 mm3/mm (p = 0.045), calcified plaque increased 0.096 mm3/mm (p = 0.001) and total plaque increased 0.249 mm3/mm (p = 0.019) whereas SBP ranging from 95 to 154 mmHg did not predict plaque volume. CONCLUSIONS Level of DBP predicts coronary plaque with a DBP tertile ≤68 mmHg associated with the least amount of coronary plaque in subjects with LDL-C < 80 mg/dL.

Resolution of NASH with weight loss documented by hepatic MRI.

A 57-year-old Asian woman with type 2 diabetes mellitus, hypertension, obesity, dyslipidaemia and history of breast cancer, was referred to the cardiovascular health and lipid centre for evaluation and management of dyslipidaemia and NASH (Non-alcoholic steatohepatitis) in 2010. She originally had a detailed work up at the liver clinic for elevated liver enzymes, with no associated symptoms. Initial hepatic MRI on 22 January 2007 showed diffuse fatty infiltration quantitated at 15%. We counselled her on lifestyle modifications, including dietary measures and exercise, geared toward weight loss. Over the next 2 years, she lost 24.5 lbs; repeat hepatic MRI on 22 December 2011 showed 6% hepatic fat, which is within the normal range. This case demonstrates the efficacy of significant weight loss in the improvement and resolution of NASH. We believe that this is the first case report documenting this through liver MRI.